1. Field of the Invention
The novel acid addition salts and compositions of the present invention possess the advantageous antitumor properties of the known free base parent compound and in addition have unexpectedly high water-solubility and stability, thus allowing preparation of useful dosage forms for intravenous administration.
2. Description of the Prior Art
The acridine derivative m-AMSA [4'-9-acridinylamino)methanesulfon-m-anisidide] has been reported by Cain, et al. in Europ. J. Cancer 10: 539-549 (1974) to possess significant antitumor activity in animal tumor systems. Since then, this compound has been subjected to clinical evaluation with very promising initial results.
When an antitumor agent such as m-AMSA is employed for treating mammalian tumors, it is recognized that stability and solubility of the agent are often the controlling factor in determining route of administration and dosage forms. For instance, a water-soluble substance, as a rule, can be generally administered intravenously whereas a water-insoluble material is limited to other alternative routes of parenteral administration such as intramuscular or subcutaneous requiring solution of the drug in a pharmaceutically acceptable non-aqueous solvent or dispersion in an aqueous solvent system. A therapeutic agent having water solubility also facilitates the absorption of the agent even in nonparenteral dosage forms, i.e. tablets, capsules, etc. Thus, it is decidedly advantageous if a therapeutic agent is water-soluble, particularly when one considers that the most direct route for achieving therapeutic blood levels of a drug is by intravenous administration.
The free base form of m-AMSA has very limited solubility in water and thus cannot be used as a dosage form for intravenous administration. Attempts have been made to prepare acid addition salts to overcome this solubility problem, but the reported monohydrochloride and monomethanesulfonate salts also proved insufficiently water-soluble for practical dosage forms.
The m-AMSA formulation presently in clinical use consists of two sterile liquids which are combined just prior to use. A solution of m-AMSA base in anhydrous N,N-dimethylacetamide is contained in an ampule. A separate vial contains an aqueous lactic acid solution for use as a diluent. When mixed the resulting m-AMSA solution is administered by i.v. infusion.
While the present clinical formulation provides an intravenous dosage form, it suffers from several disadvantages. In addition to the obvious difficulties in preparing and administering the dosage form, it contains dimethylacetamide as a vehicle. Dimethylacetamide has been reported to show various toxic symptoms in animals and may thus prove to be unacceptable or undesirable as a pharmaceutical vehicle.
It is accordingly an object of the present invention to provide water-soluble, stable, therapeutically acceptable forms of m-AMSA which can be administered to mammalian hosts intravenously (as well as by other routes) and which do not contain or require dimethylacetamide as a pharmaceutical vehicle. This object as well as other features and advantages of the invention will be readily apparent to those skilled in the art from the disclosure set out below.
The pyroglutamic acid (2-pyrrolidone-5-carboxylic acid) used as a starting material for the salts of the present invention or as a component of the compositions of the present invention has been reported in U.S. Pat. No. 3,920,814 to potentiate the intrinsic activity and blood levels of certain antibiotics such as penicillin G, pencillin V, ampicillin, cephalothin, gentamycin, tetracycline, etc. That patent also notes that pyroglutamic acid has been reported useful as a medicament for its good psyconormalizing, psychotonic, mood elevating and antitoxic action. Various other patent and literature references disclose pyroglutamate salts including, for example, Boll. Chim. Farm 116 (12): 735-743, 1977 (DL-pyroglutamate salt of L-arginine), Arzneim.-Forsch. 27 (8): 1553-1557, 1977 (DL-pyroglutamate salt of L-arginine), Japanese Published Patent Application 50/135,212 (DL-2-pyrrolidone-5-carboxylic acid triethanolamine salt as component in pruritis treatment ointment), Japanese Patent No. 74/27,643 (triethanolammonium DL-pyroglutamate as ingredient in shampoo composition), U.S. Pat. No. 3,899,585 (pyroglutamic acid salts of amino acid higher alkyl esters as fungicidal and bactericidal agents; see also U.S. Pat. No. 3,821,403), U.S. Pat. No. 3,947,589 (pyroglutamic acid salts of N-higher aliphatic acyl amino acids for use as fungicidal compositions), Japanese Patent No. 74/14,630 (DL-pyroglutamic acid salts of amino acid alkyl esters for use as fungicides), U.K. Patent No. 1,352,420 (discloses N-cocoyl-L-arginine ethyl ester DL-2-pyrrolidone carboxylate as antimicrobial or germicidal agent; see also West German Published Patent Application No. 2,131,404, Japanese Patent No. 76/22,055, Japanese Patent No. 76/5413, Oyo Yakuri 11 (6): 945-953, 1976, Yukagaku 25 (7): 404-408, 1976, Mem. Tokyo Univ. Agric 20, 51-73, 1978, Japanese Patent No. 78/118,516 and Nippon Nogei Kagaku Kaishi 52 (3): 117-121, 1978).